Process for preparing controlled release pharmaceutical forms and the forms thus obtained

ABSTRACT

An improved process for preparing controlled release pharmaceutical forms comprises exposing a mixture comprising one or more excipients and one or more active ingredients compatible with each other and with said excipients to mechanical or electromechanical actions for a well established time and within a wide range of frequencies to give tablets, matrices or mono or multilayered films. Said forms can be optionally crushed to give a granulate or powder. Depending on the employed excipient, a delayed or rapid but always controllable release of the active ingredient can be attained.

This application is a 371 of PCT/IT93/00136 filed Dec. 23, 1993.

TECHNICAL FIELD

The present invention relates to an improved process for preparingpharmaceutical forms with controlled release of the active ingredientand the forms thus obtained. More particularly, it relates to a processfor preparing pharmaceutical forms with delayed or rapid release of theactive ingredient, said delayed or rapid release being achieved byselecting appropriate excipient(s) to be mixed with the drug(s) andsubjecting the mixture thus obtained to mechanical or electromechanicalactions for a well established time and within a wide range offrequencies. The present invention elates also to the forms thusobtained, which can be administered by oral, topic or parenteral route,and which can be used also in veterinary field or, when for releasingvegetal hormones, pesticides, fragrances, preservants, also inagroindustrial field.

BACKGROUND ART

The controlled release of an active ingredient from a pharmaceuticalform containing it, is well known in the art. Generally, said systemscontain one or more excipients which modulate the release acting asdisgregating agents or as solubilizers, wetting agents etc., and/or oneor more polymeric materials acting as excipients or barriers limitatingthe release and capable to control the release rate of the therapeuticagent. Said excipients should be logically compatible with the activeingredients and the administration site, stable in the action site,capable to interact with the active ingredient and the biologic fluidsso as to provide the desired release control. They should be also easyavailable and not expensive. It is thus evident that the search forexcipients always more sophisticated and adaptable to the differentrequirements is not presently ended. This is due both to the diversityand sometime complexity of the drugs to be used, and to the desire toobtain pharmaceutical forms even more sophisticated and reliable.

Thus in U.S. Pat. No. 2,828,206 discrete, free flowing particles aredescribed, each comprising at least one inner core of fat-solublevitamin material, said core being coated with a shell of a fat-insolublesubstance selected from the group consisting of protein, gums,carbohydrates and pectin, which is in turn coated with a member of thegroup consisting of fats and waxes having a melting point between 45°and 95° C.

GB-A-1,044,572 claims a pharmaceutical composition providing prolongedrelease of a drug in the gastro-intestinal tract comprising a multitudeof medicinal pellets randomly coated with a fatty acid coatingcomprising a saturated fatty acid or mixture of saturated fatty acidshaving from 12 to 22 carbon atoms per molecule, said coating beingmodified by an inert dusting powder which serves to form channels orpores through the otherwise continuous coating.

In U.S. Pat. No. 4,341,759 granules containing a pharmaceutically activematerial and at least one pharmaceutically inactive release controllingcomponent are described, wherein said granules have a core and an outerlayer comprising at least one active compound and at least one inactiverelease controlling substance over a period of time sufficient to causesaid unitary layer to form on each core to give granules of size 0.3-2mm.

U.S. Pat. No. 4,572,833 relates to a method for preparing apharmaceutical oral controlled release composition, in which individualunits comprise units of an active substance which is subject tocontrolled release as a result of coating the units with a substantiallywater--insoluble but water-diffusable controlled release coatingcomprising applying, on units comprising the active substance, afilm-coating mixture comprising a solvent, a film-forming substancedissolved in the solvent and a hydrophobic substance substantiallymicro-dispersed in the film-coating mixture in a molten, but undissolvedstate, the film-coating mixture being applied at a temperature above themelting point of the hydrophobic substance.

U.S. Pat. No. 3,078,216 describes an oral pharmaceutical preparationhaving a prolonged release comprising a plurality of medicamentgranules, substantially all being from 12 mesh to 80 mesh, each coatedwith a layer of water insoluble, partly digestible hydrophobic material,the thickness of coating varying directly with particle size whereby inoral use the very fine granules rapidly release their medicament and thegranules of increasing size release their medicament more and moreslowly.

In U.S. Pat. No. 3,922,339 a process of preparing a sustained releasepharmaceutical preparation of a medicament is described, which comprises(1) blending a medicament with desired inert materials, (2) wetting theblend with sufficient liquid material so as to act as a binder oncompacting, (3) compacting the wetted blend by extruding to form aspaghetti-like material, (4) drying, breaking and screening the extrudedmaterial to the desired particle size, (5) spraying the particles with asolution of a film-forming material, (6) dusting the sprayed particleswith a powder and drying to form a seal on the particles, and (7)coating the sealed particles with a solution of an excipient so as toform an enteric-soluble coating on the sealed particle.

From U.S. Pat. No. 3,432,593 a granule, capsule or tablet is known,having the active medicament adsorbed on a complex colloidal magnesiumaluminum silicate. The individual granules may be further provided withone or more suitable retardant coatings, each of which provides apredetermined period of sustainment.

Further details concerning the preparation of pharmaceutical forms withcontrolled release of the active substance are reported for example inU.S. Pat. Nos. 3,137,630 and 8,492,397 as well as in EP-A-123,470.

From what stated above, it is clear that the controlled releasetechnique has been widely used and studied, but the attempts to effectnew improvements thereon go on unceasingly. Generally, the methodsutilized for having suitable matrices inglobating the active ingredientare: compaction with pressure, granulation, extrusion and thefilm-forming procedure.

However, each of the above mentioned methods has many disadvantages. Sodry compaction is possible only with suitable materials, requires theuse of specific excipients which not always are compatible with thepossible therapeutic uses, and is quite complex, requiring ratherexpensive apparatus. The wet granulation exposes the drug and theexcipients to the deleterious water and heat action, is long andexpensive and normally requires the use of binders that could interferewith the biodisponibility of the drug.

Also the film-forming procedure exposes the active ingredient and theexcipients to the deleterious action of heat, water or other solvents;it needs long time and is expensive. Extrusion is then possible onlywith materials able to assume a plastic consistency with heat andsubmits thus the active ingredient and the excipient to a prolonged andpotentially deleterious heating.

There at least to note that in the controlled release pharmaceuticalforms the release kinetic is not always optimal. Often said release isin fact too slow or too rapid, that is not controlled. Said dosage formsare thus not free from problems, in that the need a high administrationrate and can cause high fluctuations of drug in ematic and tissueconcentrations and toxic effects arising from overdosage, with onset ofthe risk of severe side effects. In other cases a deficient therapeuticefficacy can be observed, arising from an insultable release kinetic orfrom a low user's compliance, that is from the non-taking of the drugwhen said taking is too frequent, unpleasant for the patient or causesnegative side effects due to high peaks of ematic concentration of thedrug.

Attempts have been made to solve at last partly all these problemsemploying ultrasonic energy. Thus in EP-A-0 467 743 a process forcompacting a powder mixture is described, in which a non-thermoplasticproduct is blended with a thermoplastic one and the mixture thusobtained is submitted to ultrasonic energy with pressure. An adsorbingtablet is thus formed that can be imbued with a perfume and applied onthe skin, or an adsorbing strip which can be imbued with a drug.

In U.S. Pat. No. 4,657,543 a process for delivering a biologicallyactive substance on a demand is described, said process comprising thesteps of combining a biologically active substance with a biocompatiblepolymeric composition as an admixture, forming said admixture into ashaped, solid polymeric matrix, implanting said solid polymeric matrixin vivo at a preselected site such that said solid implanted matrix isin a liquid environment, and exposing said implanted solid polymericmatrix to ultrasonic energy for a predetermined time to effectcavitation of said solid polymeric matrix by rapid compression withsubsequent expansion of liquid or solid surrounding said solid polymericmatrix thereby to control the rate of release of said biologicallyactive substance from said matrix over a specific time period whereinthe rate of release is changed during said time period.

From U.S. Pat. No. 4,779,806 a process for delivering a composition ondemand is at last known, which comprises incorporating said compositionwithin a polymeric matrix, surrounding said composition and polymericmatrix with a liquid medium, and exposing said polymeric matrix toultrasonic energy for a predetermined time and at a frequency to effectcavitation of said polymeric matrix to release said composition fromsaid matrix in a controlled manner over a specific time period.

In all the literature mentioned above, with controlled release of a drugalmost always a delayed release is meant, that is a release that permitsthe drug to be released slowly to the body. In both the last mentionedUS patents use was then made ultrasonic energy for having cavitation ofa polymeric matrix, but also in this case a delayed release is achievedand it is necessary to implant a matrix in vivo and to degrade thematrix for having the desired release. It is also known that cavitationexhibits a few disadvantages, the main of which is a loss of efficiencyand risk for the health

DISCLOSURE OF INVENTION

It was thus object of the present invention to overcome thedisadvantages mentioned above and to provide an improved process forobtaining pharmaceutical forms with controlled release of the activeingredient. In particular, it was object of the present invention toprovide pharmaceutical forms from which the active ingredient could bereleased in a delayed or rapid but controlled manner based upon thechoice of the excipients, and that could be prepared in a simple waywithout employing solvents or using a prolonged heating, and that couldbe used with the most drug presently utilized in both the normal and thecontrolled release compositions.

This aim could be surprisingly attained by means of mechanical andelectromechanical actions with frequency ranging from 1 kHz and 2 MHzapplied on a mixture comprising the active ingredient and one or moreexcipients selected in such a way to obtain a form suitable for theadministration routes mentioned above.

The present invention provides accordingly an improved process forpreparing pharmaceutical forms for oral, topical or parenteraladministration with controlled release of the active ingredient, saidform comprising a mixture consisting of selected excipients and one ormore active ingredients compatible each other and with said excipients,characterized in that one or more excipients are mixed with one or moreactive ingredient compatible each other and with said excipients, andthe mixture thus obtained is exposed to mechanical or electromechanicalactions for a well established time and of frequency between 1 kHz and 2MHz to give a matrix, a tablet or a mono or multilayered film which isable to release the active ingredient in the stomach, in gut or forcontact to the skin or in a body fluid in slow or rapid but controllablemanner.

If it is desired, the matrix, tablet or mono or multilayered film can besubjected to crushing according to usual methods to give pellets orgranules having a diameter of 2.5 mm at most, which then could beinserted in usual capsules and as such they are pellets or granules ableto release the active ingredient therein contained in a delayed or quickbut always controlled manner.

Further object of the present invention are also the pharmaceuticalforms thus obtained and their use in human or veterinary field for theoral, topical or parenteral administration, or in agroindustrial fieldfor the controlled release of for example pesticides, vegetal hormones,fragrances and the like,

The frequency of the mechanical or electromechanical actions utilizedfor the practice of the present invention is normally ranging from 1 kHzto 2 MHz.

The mechanical and electromechanical actions are usually applied for abrief period of time, usually for a period of from 1/10 to 20 seconds.Based upon the length of time and frequency, tablets or matrices will beobtained having a diameter of 2-15 mm, or mono or multilayered filmswith a size of from 4 mm to 30 cm, while in every form the thicknesswill range of from 0.1 to 10 mm. The thickness will depend on the activedrug, the desired release time and on the employed excipient(s). Asmentioned above, the tablet, matrix or mono or multilayered film can beeventually subjected to a further size reduction (crushing) to givegranules having a diameter of 2.5 mm at most, which are then introducedin hard gelatine capsules or blister and are able to release the activeingredient in slow or rapid manner, while they are more soluble than theusual powders containing the same drugs and do not present dosagelimits. The pharmaceutical composition in granulate or powder form hasthe great advantage that it can be supplied by the manufacturer to everyperson having in mind to prepare pharmaceutical forms of different type(tablets, capsules, suspensions, etc.).

Further to the introduction in hard gelatine capsule, the powders andgranulates are able to be processed to give different compositions wellknown to a person skilled in the art and they do not weigh heavily uponthe final cost.

It is evident that the improvements attained with the aid ofpharmaceutical forms object of the present invention are noteworthy. Infact it is not necessary to turn to the usual methodologies such as wetor dry granulation, film-forming and so on for obtaining the desiredrelease of the drug. With the process of the invention it is in factsufficient only to select the active ingredients (s) and then expose thewhole to mechanical or electromechanical actions. With said term, anycompression effect is meant, mainly perpendicular to the treatment plane(even though not necessarily), which is able to provide a reduction ofthe bulk density, a temporary heating, changes or permeations of activeingredients and excipients lattice. Under the mechanical orelectromechanical actions term, the processes able to provide energy infrequency are included, such as ultrasonic energy, and all thosecompression and compaction procedures which could be generated alsooperating beyond the frequency limits mentioned above. As previouslydescribed, the product thus obtained can be eventually crushed andemployed in powder or granulated form.

It was surprising to find that, based upon the employed excipient, adelayed or rapid but controlled release of the drug can be attained.Thus, by employing for example well known polymers, a delayed releasewill be obtained, whereas by selecting another excipient a much morerapid release will be achieved. Illustrative examples of said excipientsallowing to have a rapid release are the solid sugars and cyclodextrins.Preferred sugars are for example lactose, fructose, maltose, arabinoseand saccharose, and the cyclodextrins are selected from the groupconsisting of α-cyclodextrin, β-cyclodextrin, Γ-cyclodextrin orderivatives thereof, or a mixture thereof.

Illustrative examples of biologically active substances which can beevenly distributed in the matrix employing the mechanical orelectromechanical actions are: vitamins, enzymes, antibiotics (such astetracyclines, penicillins, cephalosporins), diuretics, sedatives,analgesics, bronchodilators, carotenoids, β-blockers, antinflammatorics,anti-depressives, antidiabetics, lipids, antihypertensives,vasodilators, vasoconstrictors, hormones, steroids, antihistamines,antitussives, alkaloids, amino acids, antipyretics, antibacterialagents, amphetamins, hypnotics, tranquilizers, symphatomimetics,barbiturics, anti-parkinson agents, antimalarials, antispasmodics,several topic ophtalmic drugs and so on. Also interferon, antigens,antibodies, polysaccharides, growth factors, anticancer agents,phytohormones, pesticides, pheromones, fragrances, preservants, etc.

Typical examples of suitable drugs include: dexamethasone, prednisolone,isoproterenol, propranolol, codeine, atropine, hyoscyamine, morphine,streptomycin, cortisone, isosorbide-5-mononitrate, amobarbital,scopolamine, theophylline, ephedrine, urapidil, ketoprofen, paracetamol,indomethacin, diltiazem, diacerhein, phenylpzopanolamine and biliaryacids.

The polymers or copolymers useful for preparing the matrix, which can beutilized alone or in any mixture thereof, comprise all those alreadyemployed in the controlled release pharmaceutical compositions, forexample cellulose and its derivatives, polymides, acrylic polymers,polyesters, polyvinylpyrrolidone, starch, polyethylene glycols,polystyrene, polyvinylalcohol, myristyl alcohol and stearyl alcoholpolymers, polyvinyl acetate, polybutadiene, polyvinyl formal,polyvinylbutyral, vinyl chloride-vinyl acetate copolymer, ethylene-vinylacetate copolymer, vinyl chloride-propylene-vinyl acetate copolymer andany mixture thereof. The present invention is not restricted to theemployed polymers or active ingredients.

In order to evaluate the efficiency of the new formulation object of thepresent invention, tablets having a 6 mm diameter and a thickness of 4mm, each containing a suitable water soluble substance and a waterinsoluble drug, have been prepared. First, a test was performed forascertaining whether any decomposition of the active ingredientoccurred: the tablets obtained by exposing the excipient/drug mixture tomechanical or electromechanical action, have been tested for the invitro release rate in aqueous medium. In all the evaluated cases, activeingredient revealed to be absolutely unchanged. The microscopeevaluation allowed moreover to ascertain a homogenous distribution ofthe drug in the matrix. Furthermore, the crystallographic andthermographic tests have evidenced chemical-physical interactions andreticular compenetration not achievable with other compaction proceduresusually employed in pharmaceutical field. Analogous effects have beennoticed also in the majority of the other compactates obtained usingthis procedure.

For further evaluating the efficacy of the new formulations according tothe present invention, tablets having a 11 mm diameter e 4 mm thicknesswere prepared, each tablet containing suitable water soluble excipientsand active ingredients with different water solubility. The tablets werethen crushed to give pellets having a diameter of from 0.9 to 1.2 mm.First, it was ascertained whether any alteration of active ingredientdid occur; to this end, the powder obtained by electro-beating actionwas examined for the release rate in vivo in aqueous medium. The activeingredient revealed to be fully unchanged in all the tested samples, andthis in an extent of 99.5%. The electronic microscope evaluation allowedthen to ascertain an "interstitial" distribution of the drug in thematrix (FIG. 5). Comparison with the dirtibution of a drug in a standardtablet is clearly evident (FIG. 6).

It has benn further verified that the release rate can be modified atwill by adding a small amount of a substance able to modifyhydrophily-lipophily of the composition to the mixture activeingredient/excipient. Said substances can be selected from the groupconsisting of polyethylene glicol, fatty acids and their salts, talc,paraffins, waxes, hydrogenated fats, gelatin, gum arabic, agar, albumin,gluten and triglycerides. Without being bound to any theory, it isbelieved that said additive under mechanical or electromechanical actionmelts and soakes the solid, surrounding matrix, thus modifying stronglythe water penetration rate and thus dissolution rate and drugbioavailability.

Logically, the release kinetic can be regulated at will by varying theamount and/or nature of the polymeric materials and/or excipientsemployed for obtaining the matrix. The relative proportions of thecomposition to be exposed to mechanical or electromechanical action canbe modified over a wide range depending upon the active ingredient to beadministered or the desired effect. Generally, the active ingredient canbe present in an amount which will be released over controlled periodsof time, according to predetermined desired rates, which rates aredependant upon the initial concentration of the active ingredient in thematrix and the level of mechanical or electromechanical action to whichit is subjected. Proportions suitable for the purpose of this inventioncan range from about 30 to 75% by weight of active ingredient and about70 to 25% by weight of excipient(s) to give 100% by weight of the finalsystem.

It is also clear that any person skilled in the art could modify thepresent invention utilizing another drug or different substances forhaving the synthetic matrix. It appears thus to be superfluous to pointout as such modifications belong in toto to the invention as describedabove, and therefore they could not be retained as different from theclaims as reported here below.

BRIEF DESCRIPTION OF THE DRAWINGS

To show the efficacy of the employed method, comparisons between the newpharmaceutical forms and those obtained by usual compaction were carriedout. The results will be discussed in the following examples and in theaccompanying drawings. In said drawings, FIGS. 1-4 are explained in theExamples, whereas

FIG. 5 is a microphotograph of a section of a tablet containingexcipients+active ingredient: Korsch apparatus, compression power 5000kg/cm² ; and

FIG. 6 is a microphotograph of the same composition as in FIG. 5, butsubjected to compaction according to the invention.

The forms object of the present invention are illustrated in thefollowing Examples. Since the Examples are for illustrative purposes,they should not be construed as limiting. All "%" are by weight unlessotherwise specified.

EXAMPLE 1

This example shows the increase of the dissolution rate of the activeingredient contained in a solid oral formulation.

A mixture comprising 68% spray-dried, free flowing lactose (able to bedirectly compressed), 30% indomethacin (particle diameter: 60% <85 μm;98% <105 μm), 1% talc and 1% magnesium stearate, was homogenously workedin a Turbula T2C® mixer.

Said mixture was then divided in two portions, one of which wascompressed at a compression force of 35,000 N/cm² by means of analternative Korsch EKO® apparatus to give tablets having a 11 mmdiameter and a weight of 350 mg (tablet A). The other portion wascompacted according to the invention (tablet B, frequency 30 kHz, energy400 J). Strength, measured with a Monsanto apparatus, resulted to be 5kg for tablet A and 7.5 kg for tablet B.

Both tablets A and B were subjected to the in vitro dissolution test ina laminar flow column dissolver operating at open circuit and employinga buffer solution of pH 7.4 as dissolution medium (flow=12,5 ml/min at37° C.).

Curves a and b in FIG. 1 show the amount of indomethacin gone insolution (mg) vs time for tablets A and B respectively (each point ofsaid graphs shows the average value obtained in 5 tests). As it is clearfrom said graph, with the formulation compacted according to the presentinvention a dissolution rate of more than 100 fold can be obtained (100%quicker).

EXAMPLE 2

In this Example the preparation of a prolonged release granulate isdescribed. A mixture comprising 68% of a directly comprimible EudragitRPL®, 30% anhydrous theophylline and 1% of both talc and magnesiumstearate, after treatment in Turbula T2C mixer, was divided in two equalparts. The first portion was compacted by means of an alternative KorschEKO apparatus operating at 40,000 N/cm², to give tablets having adiameter of 11 mm and weighing 400 mg±4.5% (tablet A).

The second portion of the powder was compressed according to the presentinvention by providing each tablet, weighing 400 mg±3% and having adiameter of 11 mm, with an energy of 400 J (tablet B).

The strength was as stated above in Example 1 (5 kg±2%).

Both tablets A and B were separately transformed in a granulate by meansof a dry Erweka TG II S granulator, and both the granulates were thenclassified in a vibrating screen, keeping the fractions having adiameter of 100 and 150 μm, denominated granulate A and B respectively.

FIG. 2 shows the dissolution curves (cumulative % of releasedtheophylline) for granulate A (a curve) and B (b curve) respectively, asmeasured in a laminar flow column dissolver operating at open circuitand at 37° C., using a buffer solution of pH 7.4 as dissolution medium(flow=12.5 ml/min).

As evident, the dissolution rate is clearly lower for granulate B and ananalogous difference in the dissolution rate can be ascertained for thetablet obtained by compaction of granulate A and B in an alternativeapparatus.

EXAMPLE 3

In this Example the preparation of prolonged release monolithiccompactates is described. First, a mixture comprising equal amounts ofEudragit RS and Eudragit RLP (both these materials being able to beemployed in direct compression) was prepared, and it was made homogenousby treatment in a Turbula T2C mixer for 10 minutes. This compositepowder was thereafter referred as powder A.

The following mixtures were then prepared:

30% anhydrous theophylline, 68% powder A, 1% of both talc and magnesiumstearate (mixture B);

50% anhydrous theophylline, 48% powder A, 1% of both talc and magnesiumstearate (mixture C);

75% anhydrous theophylline, 23% powder A, 1% of both talc and magnesiumstearate (mixture D). Each of the mixtures thus obtained was treated ina Turbula T2C mixer and then it was compacted according to the inventionsubjecting each tablet, having a diameter of 11 mm and weighing 400 mg,to an energy of 400 J (frequency 30 kHz). Tablets Bm, Cm and Dm werethus obtained.

A portion of mixture B was then compacted in an alternative Korsch EKOapparatus operating at 3500 N/cm² to give tablets of 400 mg and with adiameter of 11 mm (tablets Bk).

FIGS. 3 and 4 show the dissolution rate vs time (mg of theophylline) fortablets Bm, Cm, Dm and Bk in a laminar flow column dissolver (12.5ml/min and 37° C.) operating at open circuit at pH 1 (FIG. 5) and pH 7.4(FIG. 6).

Tablets obtained with the process of the present invention exhibit aclearly lower release rate which is equivalent to the in vitro releaseof both tablets Cm and Bk, notwithstanding they differs about 100% inthe high water soluble theophylline content. The process of the presentinvention allows moreover to compact easily mixtures with high anhydroustheophylline content, which are unsuitable for a direct compression.

I claim:
 1. A process for preparing controlled release pharmaceuticalforms, characterized in that a mixture containing from 30 to 75% byweight of an active ingredient and from 70 to 25% by weight of one ormore excipients is compacted by means of mechanically orelectromechanically generated ultrasonic energy, said ultrasonic energyhaving a frequency of up to 2 MHz and being emitted for a period of timeof from 1/10 to 20 seconds, to give a tablet, matrix, simple ormultilayer film, said tablet or matrix having a diameter of from 2 to 15mm and said film a size of from 4 mm to 30 cm, the thickness beinggenerally of 0.1 to 10 mm.
 2. A process according to claim 1, furthercharacterized in that said tablet, matrix or film is then submitted topelletization to give pellets having a diameter of 2.5 mm at most stillmaintaining unaltered the ability of a controlled release of the activeingredient.
 3. A process according to claim 1, characterized in that thefrequency of the mechanically or elctromechanically generated ultrasonicenergy is 30 kHz.
 4. A process according to claim 1, characterized inthat for having delayed release of the active ingredient the excipientis a polymer or copolymer selected from the group consisting ofcellulose, polyamide, acrylic polymer, polyester, polyvinylpyrrolidone,polyethylene glycol, polystyrene, polyvinylalcohol, vinyl chloride-vinylacetate copolymer, ethylene-vinyl acetate copolymer, vinylchloride-propylene-vinyl acetate copolymer, polyvinylformal,polyvinvylacetate, polybutadiene, polyvinylbutyral and mixtures thereof.5. A process according to claim 1, characterized in that the excipientis selected from the group consisting of sugars, cyclodextrins andmixtures thereof.
 6. A process according to claim 5, characterized inthat the sugar is selected from the group consisting of lactose,maltose, saccharose, fructose, arabinose or a mixture thereof.
 7. Aprocess according to claim 5, characterized in that cyclodextrins areselected from the group consisting of alpha-cyclodextrin,β-cyclodextrin, gamma-cyclodextrin, and mixtures thereof.
 8. A processaccording to claim 1, characterized in that for modifying the releaserate at will, a substance able to inluence the hydrophily/lipophily ofthe composition and selected from the group consisting of polyethyleneglycol, fatty acid and their salts, talc, gelatin, gum arabic,hydrogenated fats, agar, albumin, gluten and triglycerids is added tothe excipient/active ingredient mixture.
 9. A process according to claim1, characterized in that the mixture to be compacted by means of themechanically or electromechanically generated energy comprises one ormore active ingredients compatible with each other.
 10. Pharmaceuticalform with controlled release of the active ingredient for oral, topicalor parenteral administration, said form being a tablet, matrix or monoor multilayered film, characterized in that it is obtained by compactingwith the aid of pressure and mechanically or electromechanicallygenerated ultrasonic energy of frequency between 1 kHz and 2 MHz and fora period of time of from 1/10 to 20 seconds a mixture comprising from 30to 75% by weight of an active ingredient and from 70 to 25% by weight ofone or more excipients.
 11. Pharmaceutical form according to claim 10,characterized in that is obtained by compacting by means of mechanicallyor electromechanically generated energy and pressure a mixturecomprising the active ingredient and or more excipients compatible witheach other, the frequency of said ultrasonic energy being 30 kHz. 12.Pharmaceutical form according to claim 10, characterized in that it hasa diameter of from 2 and 15 mm if tablets or matrix and a size of from 4mm to 30 cm if it is a film, and generally a thickness of from 0.1 to 10mm.
 13. Pharmaceutical form with controlled release of the activeingredient, characterized in that it is a pellet having a particle sizeof 2.5 mm at most, which can be used as such or inserted in hardgelatine capsules, and is obtained by crushing the tablet, matrix orfilm prepared compacting by means of pressure and electrically orelectromechanically generated energy having a frequency between 1 kHzand 2 MHz, and emitted for a period of time of from 1/10 to 20 seconds,a mixture comprising from 30 to 75% by weight of the active ingredientand from 70 to 25% by weight of one or more excipients compatible witheach other.
 14. Pharmaceutical form according to claim 10, to beemployed also in veterinary field.
 15. Pharmaceutical form according toclaims 10, to be employed also in agroindustrial field. 16.Pharmaceutical form according to claim 10, characterized in that itcontains one or more polymers or copolymers compatible with each otherand with the active ingredient, or it contains one or more excipientscompatible with each other and with said active ingredient. 17.Pharmaceutical form according to claim 16, characterized in that itcontains one or more excipients selected from the group consisting oflactose, fructose, maltose, arabinose, saccharose, α-cyclodextrin,β-cyclodextrin and γ-cyclodextrin.
 18. Pharmaceutical form according toclaim 16, characterized in that for delayed release the excipient isselected from the group consisting of cellulose, polyamide, acrylicpolymer, polyester, polyvinylpyrrolidone, polyethylene glycol,polystyrene, polyvinyl alcohol, vinyl chloride-vinyl acetate copolymer,ethylene-vinyl acetate copolymer, vinyl chloride-propylene-vinyl acetatecopolymer, polyvinyl formal, polyvinylacetate, polybutadiene, polyvinylbutyral, and mixtures thereof.
 19. Pharmaceutical form according toclaim 10, characterized in that for modifying the release rate at will,a substance able to modify the hydrophily/lipophily of the compositionand selected from the group consisting of polyethylene glycol, fattyacids and their salts, talc, gelatin, gum arabic, hydrogenated fats,agar, albumin, gluten and triglycerides is added to the excipient/activeingredient mixture.
 20. The pharmaceutical form of claim 13, wherein theelectrically or electromechanically generated energy has a frequency of30 Khz.